Although the genetic cause of cystic fibrosis (CF), a lethal autosomal disorder, has been known for over a decade, an effective therapeutic method is still lacking. Pulmonary disease remains the major cause of morbidity and mortality in CF. The CF lung is marked by dysregulated inflammation and chronic infection, the end result being progressive bronchiectatic destruction of the airways. The airway inflammatory response in CF is persistently neutrophilic; in turn, products of activated neutrophils appear to be largely responsible for airway destruction. Despite progress in CF therapy in recent decades, the norm is still an inexorable decline in pulmonary function, leading eventually to death or to a need for lung transplantation. There is thus a pressing need for an effective, safe method for suppressing aberrant airway inflammatory responses in CF. We have found that levels of certain endogenous lipid mediators have beneficial effects in a well-characterized mouse model of the airway inflammation and infection of CF. These data suggest that such lipid-based mediators have therapeutic potential in CF. The ultimate goal of this program is to develop a lipid-based therapy for CF, based on these findings. We aim to validate the viability and feasibility of treating pulmonary inflammation in CF by: (1) confirming and extending our preliminary data indicating therapeutic benefit in mouse models of CF-related chronic infection and inflammation using appropriate lipid derivatives, and (2) designing and synthesizing improved lipid analogues and testing the feasibility of scale-up of selected analogues for preclinical evaluation and further studies. If successful, these studies will provide the basis for pursuing preclinical and clinical studies in this area.